WO2018181963A1 - リポソーム組成物および医薬組成物 - Google Patents

リポソーム組成物および医薬組成物 Download PDF

Info

Publication number
WO2018181963A1
WO2018181963A1 PCT/JP2018/013783 JP2018013783W WO2018181963A1 WO 2018181963 A1 WO2018181963 A1 WO 2018181963A1 JP 2018013783 W JP2018013783 W JP 2018013783W WO 2018181963 A1 WO2018181963 A1 WO 2018181963A1
Authority
WO
WIPO (PCT)
Prior art keywords
liposome
aqueous phase
drug
liposome composition
composition according
Prior art date
Application number
PCT/JP2018/013783
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
典之 笠置
山田 直樹
幹永 森
加藤 貴之
貴之 小林
Original Assignee
富士フイルム株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2019509395A priority Critical patent/JP6728482B2/ja
Priority to EP18776957.5A priority patent/EP3603620A4/en
Priority to BR112019020406-7A priority patent/BR112019020406B1/pt
Priority to CN202310994904.XA priority patent/CN116763734A/zh
Application filed by 富士フイルム株式会社 filed Critical 富士フイルム株式会社
Priority to CN201880023073.9A priority patent/CN110505869A/zh
Priority to CN202310994903.5A priority patent/CN116763733A/zh
Priority to KR1020197028183A priority patent/KR102328463B1/ko
Priority to CN202111595172.4A priority patent/CN114224840A/zh
Priority to CA3058127A priority patent/CA3058127C/en
Priority to RU2019130500A priority patent/RU2734900C1/ru
Priority to AU2018246024A priority patent/AU2018246024B2/en
Publication of WO2018181963A1 publication Critical patent/WO2018181963A1/ja
Priority to US16/583,518 priority patent/US11413244B2/en
Priority to US17/079,759 priority patent/US11446247B2/en
Priority to US17/882,144 priority patent/US20220370352A1/en

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1271Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1271Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/02Ammonia; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a liposome composition and a pharmaceutical composition exhibiting high blood retention.
  • a liposome composition as a pharmaceutical composition, a drug is encapsulated in a liposome composed of a lipid membrane.
  • Patent Document 1 and Non-Patent Document 1 describe liposomes in which topotecan is encapsulated in liposomes containing sphingomyelin and cholesterol.
  • Patent Document 2 describes a liposome in which topotecan is encapsulated in a liposome containing dihydrosphingomyelin and cholesterol.
  • Patent Document 3 discloses a liposomal camptothecin preparation adapted to enhance the stability of camptothecin, wherein (a) camptothecin encapsulated in the liposome, (b) outside the liposome, pH less than 4.5 or A formulation comprising a first solution that is 5 and (c) a second solution that is inside a liposome is described. It is also described that the liposome contains dihydrosphingomyelin and cholesterol.
  • Patent Document 4 discloses a system for effectively filling an amphipathic drug into liposomes, in which a liposome suspension is prepared in the presence of an ammonium compound or an ammonium salt, and the suspension is diluted with a buffer or a salt. And providing an ammonium gradient from the inner side to the outer side between the inner aqueous phase and the outer aqueous phase, and a pH gradient such that the pH inside the liposome is more acidic than the outside pH, The system is described.
  • Patent Document 5 describes a liposome in which topotecan is encapsulated in a liposome containing purified hydrogenated soybean phospholipid or sphingomyelin, cholesterol and a hydrophilic polymer derivative lipid in the presence of ammonium sulfate.
  • topotecan is encapsulated in liposomes containing sphingomyelin or dihydrosphingomyelin to suppress the outflow of topotecan in the blood, and AUC (Area Under) It is described that the drug effect is improved by improving the blood concentration-time curve (the area under the blood concentration-time curve).
  • AUC Absolute Under
  • topotecan when topotecan leaks from the inner aqueous phase of the liposome to the outer aqueous phase and is exposed to neutral conditions, topotecan changes to an analog. Specifically, an N—N ⁇ ⁇ bis adduct (topotecanamine dimer) having extremely low solubility may precipitate and precipitate as crystals. Ultimately, many insoluble particulates are produced that deviate from the safety and quality standards set forth by US Food and Drug Administration (FDA), Japanese Pharmaceutical and Medical Device Agency (PMDA), and European Medicines Agency (EMEA). It is not preferable. In order to suppress the generation of such insoluble fine particles, in Patent Document 3, the pH of the outer aqueous phase is set to an acidic condition.
  • FDA US Food and Drug Administration
  • PMDA Japanese Pharmaceutical and Medical Device Agency
  • EMEA European Medicines Agency
  • the present inventors have used diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer as constituents of the liposome membrane.
  • the phase contains ammonium sulfate and that the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is 0.36 or more can provide a liposome composition that solves the above problems. It came.
  • a liposome composition comprising diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer as a component of the liposome membrane, the liposome composition encapsulating a drug, and the inner aqueous phase is ammonium sulfate
  • a liposome composition having a molar ratio of inner aqueous phase sulfate ion to total aqueous phase drug of 0.36 or more.
  • the ratio of sulfate ions contained in the inner aqueous phase of the liposome to sulfate ions in the entire liposome composition is at least 80%, and the ratio of the drug contained in the inner aqueous phase of the liposome to the drug in the entire liposome composition is at least 80%.
  • the release rate of the drug from the liposome in plasma with an ammonium concentration of 1 mmol / L or less is 20% / 24 hours or less at 37 ° C.
  • the release rate of the drug from the liposome in plasma with an ammonium concentration of 4-6 mmol / L is The liposome composition according to [9], which is 60% / 24 hours or more at 37 ° C.
  • the number of particles exceeding 10 ⁇ m contained per 1 ⁇ mol of lipid in the liposome composition after storage at 5 ° C. for one month is 15 or less, and the number of particles exceeding 25 ⁇ m contained per 1 ⁇ mol of lipid in the liposome composition is 15 or less.
  • a pharmaceutical composition comprising the liposome composition according to any one of [12]. [14] The pharmaceutical composition according to [13], which is an anticancer agent. [15] A liposome composition containing diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer as components of the liposome membrane, the liposome composition encapsulating a drug, and the inner aqueous phase is ammonium A liposome composition comprising a salt, wherein the dihydrosphingomyelin is a dihydrosphingomyelin having a long-chain alkyl group having 16 and 18 carbon atoms.
  • a liposome composition comprising diacylphosphatidylethanolamine modified with a hydrophilic polymer, dihydrosphingomyelin, and cholesterols as constituents of a liposome membrane, wherein the liposome composition encapsulates a drug
  • a method for treating a disease comprising administering to a subject a liposome composition wherein the phase comprises ammonium sulfate and the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is 0.36 or more.
  • Liposome composition comprising diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer as components of the liposome membrane for use in the treatment of diseases (preferably cancer)
  • the liposome composition contains a drug, the inner aqueous phase contains ammonium sulfate, and the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is 0.36 or more.
  • a liposome composition comprising diacylphosphatidylethanolamine modified with a hydrophilic polymer, dihydrosphingomyelin, and cholesterols for producing a pharmaceutical composition, wherein the liposome composition encapsulates a drug,
  • the liposome composition encapsulates a drug
  • Use of a liposome composition, wherein the inner aqueous phase contains ammonium sulfate and the molar ratio of inner aqueous phase sulfate ions to the total aqueous phase drug is 0.36 or more.
  • the liposome composition and pharmaceutical composition of the present invention can exhibit high AUC.
  • FIG. 1 shows the measurement results of body weight in a drug efficacy test using an A549 subcutaneously transplanted mouse model.
  • FIG. 2 shows the measurement results of body weight in a drug efficacy test using an A549 subcutaneously transplanted mouse model.
  • FIG. 3 shows the measurement results of tumor volume in a drug efficacy test using an A549 subcutaneously transplanted mouse model.
  • FIG. 4 shows the measurement results of tumor volume in a drug efficacy test using an A549 subcutaneously transplanted mouse model.
  • FIG. 5 shows the AUC value for each cholesterol level.
  • FIG. 6 shows the results of measuring the dependency of ammonium ions on the release rate.
  • a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the amount of each component in the composition means the total amount of the plurality of substances present in the composition unless there is a specific notice when there are a plurality of substances corresponding to each component in the composition. To do.
  • Retention in blood means a property in which a drug encapsulated in liposomes is present in blood in a subject administered with a liposome composition.
  • the “average particle size of liposome” means a cumulant average particle size measured using a dynamic light scattering method unless otherwise specified.
  • Examples of commercially available measuring apparatuses using dynamic light scattering include a dense particle analyzer FPAR-1000 (manufactured by Otsuka Electronics Co., Ltd.), Nanotrack UPA (manufactured by Nikkiso Co., Ltd.), and nanosizer (manufactured by Malvern). It is also possible to calculate the volume average particle diameter and the number average particle diameter of the liposome by a conversion formula specific to each manufacturer's measuring apparatus. In order to measure particles near 100 nm, the static light scattering method or the like cannot accurately grasp the particle distribution, and measurement by the dynamic light scattering method is preferable.
  • “Insoluble microparticles” are items set as safety and quality standards by regulatory authorities such as PMDA, FDA, EMEA in pharmaceutical compositions for systemic administration such as intravenous injections.
  • PMDA light-shielding particle counting method
  • the particle size contained in one drug vial of a product with a displayed amount of less than 100 mL is insoluble with a particle size of 10 ⁇ m or more. It is required that the number of fine particles is 6000 or less and the number of insoluble fine particles having a particle size of 25 ⁇ m or more is 600 or less.
  • the second method microscopic particle counting method
  • the insoluble fine particles are defined only by the size of the particles, regardless of the component of the particles.
  • the insoluble fine particles may be aggregates of the liposomes themselves, or the drug components leaked from the inside of the liposomes. Aggregation and precipitation may be sufficient, and aggregation and precipitation of the component of a liposome outer water phase may be sufficient.
  • the liposome encapsulating topotecan in the present invention is known to be a precipitate formed by the encapsulation of topotecan leaking out of the liposome and decomposing into a degradation product with low solubility. It has been.
  • a light shielding particle counting method particle counter, for example, HIAC 9703+ manufactured by Beckman Coulter, Inc., Accusizer A2000USP manufactured by Particle Sizing Systems, Inc.
  • a microscopic particle counting method in which the magnified image is visually observed and counted.
  • a liposome pharmaceutical composition particularly an injectable preparation, as defined in the Japanese Pharmacopoeia ⁇ 6.07> insoluble fine particle test method for injectables
  • 6000 particles having a particle size exceeding 10 ⁇ m are included in the pharmaceutical composition when used.
  • the number of particles having a particle size exceeding 25 ⁇ m is preferably 600 or less.
  • insoluble fine particles In injectable preparations of liposomal pharmaceutical compositions, the cause of insoluble fine particles is mostly due to aggregation, coalescence, and decomposition of liposome particle components that occur during storage, but is not limited thereto. There is a tendency that insoluble fine particles are generated depending on the amount of lipid which is a main material constituting the liposome. For example, when considering a pharmaceutical composition containing 2 mL of a liposome composition having a lipid concentration of 20 mmol / L, 150 particles or less with a particle size exceeding 10 ⁇ m per 1 mol of lipid, and 15 particles or less with a particle size exceeding 25 ⁇ m.
  • the liposome composition of the present invention it is preferable that after storage for 1 month at 5 ° C., 150 particles or less having a particle size exceeding 10 ⁇ m per 1 mol of lipid and 15 or less particles having a particle size exceeding 25 ⁇ m. . More preferably, after storage for 1 month at 5 ° C., 75 particles or less with a particle size exceeding 10 ⁇ m per 1 mol of lipid and 7.5 particles or less with a particle size exceeding 25 ⁇ m.
  • coarse particles having a particle size exceeding 10 ⁇ m often increase due to deterioration over time during storage, and preferably satisfy the above number even after storage for 3 months, and satisfy the above number even after one year storage. It is more preferable.
  • Subject refers to mammals such as humans, mice, monkeys, and livestock that require prevention or treatment of diseases, and preferably humans that require prevention or treatment of diseases and the like.
  • the liposome composition according to the first aspect of the present invention is a liposome composition containing diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer as components of the liposome membrane, Encapsulated, the inner aqueous phase contains ammonium sulfate, and the molar ratio of inner aqueous phase sulfate ions to the total aqueous phase drug is 0.36 or more.
  • the liposome composition according to the second aspect of the present invention is a liposome composition containing diacylphosphatidylethanolamine modified with a hydrophilic polymer, dihydrosphingomyelin, and cholesterols as components of the liposome membrane,
  • the drug is encapsulated, the inner aqueous phase contains an ammonium salt, and the dihydrosphingomyelin is a dihydrosphingomyelin having a long-chain alkyl group having 16 and 18 carbon atoms.
  • the retention of liposomes in blood is improved by using diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer as components of the liposome membrane.
  • the inner aqueous phase contains ammonium sulfate, leakage of the drug from the liposome in the blood is suppressed, and AUC is improved.
  • the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is 0.36 or more, the leakage of the drug from the liposome in the blood is further suppressed, and a higher AUC is achieved.
  • the pH of the outer aqueous phase can be set near neutral (pH 7.4), and hydrolyzed under acidic conditions, “diacylphosphatidyl ethanol modified with a hydrophilic polymer” Amine "can be used to improve blood retention.
  • a liposome is a closed vesicle formed of a lipid bilayer membrane using lipid, and has an aqueous phase (inner aqueous phase) in the space of the closed vesicle.
  • the inner water phase includes water and the like.
  • Liposomes usually exist in a dispersed state in an aqueous solution outside the closed vesicles (outer aqueous phase). Liposomes are single lamellae (also called single-layer lamellae or unilamellar, and double-layer membranes have a single structure), but they are multi-layer lamellae (also called multi-lamellar, which have a large number of onion-like bilayer membranes). In the present invention, from the viewpoint of safety and stability in pharmaceutical use, it is a single-lamellar liposome. Is preferred.
  • the form of the liposome is not particularly limited as long as it is a liposome capable of encapsulating a drug.
  • “Encapsulation” means that the drug is in a form in which the drug is contained in the inner aqueous phase and the membrane itself.
  • a form in which a drug is enclosed in a closed space formed of a film, a form in which the drug is included in the film itself, and the like may be used.
  • the average particle size of the liposome is generally 10 nm to 1000 nm, preferably 20 nm to 500 nm, more preferably 30 to 300 nm, still more preferably 30 nm to 200 nm, and even more preferably 150 nm or less, for example, 30 nm to 150 nm. 70 to 150 nm is particularly preferable.
  • Liposomes are preferably in the form of spheres or similar.
  • the component constituting the lipid bilayer of the liposome is selected from lipids.
  • lipid one that can be dissolved in a mixed solvent of a water-soluble organic solvent and an ester-based organic solvent can be used.
  • the liposome in the present invention contains diacylphosphatidylethanolamine modified with a hydrophilic polymer, dihydrosphingomyelin, and cholesterols as components of the liposome membrane.
  • a liposome is a closed endoplasmic reticulum formed by a lipid bilayer membrane using lipid as described above.
  • a lipid as a base material for forming a lipid bilayer membrane is a phosphorous having two acyl chains.
  • Lipids such as phosphatidylcholine (lecithin), phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolipin, or hydrogenated ones (for example, , Hydrogenated soybean phosphatidylcholine (HSPC)) and the like.
  • HSPC Hydrogenated soybean phosphatidylcholine
  • a phospholipid having two acyl chains is used as a lipid serving as a base material for forming a lipid bilayer membrane.
  • dihydrosphingomyelin the retention of liposomes in blood can be improved.
  • dihydrosphingomyelin as the base material of the liposome membrane, the partition property of the liposome membrane can be improved and leakage of the encapsulated drug can be prevented. This is presumed that the amide bond of dihydrosphingomyelin has a strong hydrogen bonding ability and can form a strong and highly partitionable film by strongly interacting with each other.
  • dihydrosphingomyelin that is completely saturated has a high melting point and lowers the mobility of the formed film.
  • dihydrosphingomyelin can make a membrane having a high partitioning property.
  • Dihydrosphingomyelin generally has two long-chain alkyl groups in the molecule, two long-chain alkyl groups having 16 carbon atoms, long-chain alkyl groups having 16 and 18 carbon atoms. And those having a long-chain alkyl group having 16 carbon atoms and 20 to 24 carbon atoms.
  • dihydrosphingomyelin from the viewpoint of preventing leakage of the drug from the liposome, it is preferable to use the following compounds having a long-chain alkyl group having 16 and 18 carbon atoms. This is because the higher the number of carbon atoms, the higher the melting point and the higher the ability to make a liposome membrane.
  • dihydrosphingomyelin for example, dihydrosphingomyelin obtained by reducing sphingomyelin derived from a natural product by a general method may be used, or dihydrosphingomyelin obtained by synthesis may be used. Since dihydrosphingomyelin derived from natural products such as chicken eggs generally has two long-chain alkyl groups having 16 carbon atoms, dihydrosphingomyelin having long-chain alkyl groups having 16 and 18 carbon atoms. It is preferable to use a product obtained by chemical synthesis in that it can be obtained with high purity.
  • the proportion of dihydrosphingomyelin in the constituent components of the liposome membrane is preferably 30 to 80 mol%, more preferably 40 to 70 mol%, still more preferably 50 to 60 mol%. is there.
  • hydrophilic polymer in diacylphosphatidylethanolamine modified with a hydrophilic polymer examples include, for example, polyethylene glycols, polyglycerols, polypropylene glycols, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, polyvinylpyrrolidone, synthesis Examples include polyamino acids. Said hydrophilic polymer can be used individually or in combination of 2 types or more, respectively.
  • polyethylene glycols, polyglycerols and polypropylene glycols are preferable from the viewpoint of blood retention of the composition, and polyethylene glycol (PEG), polyglycerol (PG), polypropylene glycol (PPG) and derivatives thereof. Is more preferable.
  • polyethylene glycol (PEG) and its derivatives are more preferable.
  • PEG polyethylene glycol
  • Examples of polyethylene glycol (PEG) derivatives include, but are not limited to, methoxypolyethylene glycol.
  • the molecular weight of polyethylene glycols is not particularly limited, but is 500 to 10,000 daltons, preferably 1,000 to 7,000 daltons, and more preferably 2,000 to 5,000 daltons.
  • the carbon number of acyl in diacylphosphatidylethanolamine is preferably 16 or more, for example, preferably 16 to 30 carbon atoms, more preferably 16 to 24 carbon atoms, and further preferably 20 carbon atoms.
  • diacylphosphatidylethanolamine modified with polyethylene glycol examples include 1,2-distearoyl-3-phosphatidylethanolamine-PEG2000 (manufactured by NOF Corporation), 1,2-distearoyl-3-phosphatidylethanolamine- 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol such as PEG5000 (manufactured by NOF Corporation) and distearoylglycerol-PEG2000 (manufactured by NOF Corporation).
  • the ratio of diacylphosphatidylethanolamine modified with a hydrophilic polymer in the components of the liposome membrane is preferably 1 to 15 mol%, more preferably 2 to 10 mol%. .
  • cholesterols examples include cholesterol having cyclopentahydrophenanthrene as a basic skeleton, and part or all of which are hydrogenated, and derivatives thereof.
  • cholesterol is preferable.
  • the curvature of the lipid membrane may increase.
  • the strain of the membrane arranged in the liposome is also increased. It is effective to add cholesterol or the like in order to fill the membrane distortion caused by lipids (membrane stabilization effect).
  • the addition of cholesterol is expected to lower the fluidity of the liposome membrane by filling the gap in the liposome membrane.
  • the proportion of cholesterol in the constituent components of the liposome membrane is preferably 20 mol% to 50 mol%, more preferably 30 mol% to 45 mol%, still more preferably 35 to 43 mol%. %.
  • the liposome may be added with a hydrophilic polymer or the like for the purpose of improving blood retention, fatty acid or diacetyl phosphate as a membrane structure stabilizer, and ⁇ -tocopherol as an antioxidant. Good.
  • additives such as dispersion aids that are not approved for intravenous use in pharmaceutical applications, such as surfactants.
  • the liposome composition of the present invention contains a drug.
  • the anticancer agent illustrated below can be used. Specifically, anthracycline anticancer agents such as doxorubicin, daunorubicin and epirubicin; Cisplatin anticancer agents such as cisplatin and oxaliplatin; Taxane anticancer agents such as paclitaxel and docetaxel; Vinca alkaloid anticancer agents such as vincristine and vinblastine; Bleomycin-based anticancer agents such as bleomycin; Sirolimus anticancer drugs such as sirolimus; Camptothecin-based anticancer agents such as topotecan (also referred to as Nogitecan), irinotecan, Karenitecin (registered trademark) (also referred to as BNP1350), exatecan, roottecan, gimatecan (also referred to as ST1481) and belothecan (also referred to as
  • the drug may be used as a salt form.
  • the salt of a drug include salts that are generally known in basic groups such as an amino group and acidic groups such as a hydroxyl group and a carboxyl group.
  • salts in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, boric acid, nitric acid and sulfuric acid; formic acid, acetic acid, lactic acid, citric acid, oxalic acid, fumaric acid, malein Acids, succinic acid, malic acid, tartaric acid, aspartic acid, salts with organic carboxylic acids such as trichloroacetic acid and trifluoroacetic acid; and methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid And salts with sulfonic acid such as
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
  • alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
  • the content of the drug in the liposome composition is not particularly limited, but is preferably 0.025 to 20 mg / ml, more preferably 0.25 to 10 mg / ml with respect to the liposome composition.
  • the amount of drug encapsulated in the liposome relative to the lipid forming the liposome membrane is preferably 0.1 to 1.5 in terms of molar ratio from the viewpoint of the release rate from the liposome, the osmotic pressure inside the liposome, and the liposome shape due to the precipitated drug, 0.2 to 0.3 is more preferable.
  • the molar ratio of the drug amount to the lipid When the molar ratio of the drug amount to the lipid is too low, the area of the liposome membrane with respect to the unit drug amount is increased, so that the release rate of the drug from the liposome is increased and the function of improving the blood retention is impaired. On the other hand, if the molar ratio of the drug amount to the lipid is too high, the osmotic pressure inside the liposome rises due to an increase in the amount of drug dissolved and the liposome is destroyed, or if the drug precipitates inside the liposome The solid matter thus grown grows and the liposome shape is deformed.
  • the internal aqueous phase of the liposome in the present invention contains ammonium sulfate.
  • the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is 0.36 or more, preferably 0.4 or more.
  • the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is more preferably 0.4 or more and 1.8 or less, and still more preferably 0.6 or more and 1.8 or less.
  • the molar ratio of the internal aqueous phase sulfate ion to the total aqueous phase drug as described above, leakage of the drug from the liposome in the blood can be suppressed. If the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is too low, the formation of solids due to the sulfate of the drug will be incomplete, and the concentration of the drug in the dissolved state will increase the permeability of the liposome membrane within the liposome. The drug is likely to leak from the liposome, and the effect of improving the blood retention is impaired.
  • the ratio of sulfate ions contained in the inner aqueous phase of the liposome to the sulfate ions in the entire liposome composition is preferably at least 80%, preferably 90% or more. More preferably, at the same time, the ratio of the drug contained in the internal aqueous phase of the liposome to the total drug in the liposome composition (the internal aqueous phase ratio of the drug) is preferably at least 80%, preferably 90% or more. Is more preferable.
  • the drug concentration in the liposome can be measured by, for example, liquid chromatography / ultraviolet visible absorbance detection method.
  • the sulfate ion concentration in the inner aqueous phase of the liposome can be measured, for example, by ion chromatography.
  • the liposome composition of the present invention can comprise a liposome encapsulating a drug and an aqueous solvent (external aqueous phase) in which the liposome is dispersed.
  • the pH of the outer aqueous phase is preferably neutral, and specifically, is preferably about pH 5.5 to 8.5.
  • the liposome composition of the present invention has a surprising mechanism that suppresses drug leakage in the blood, delivers a sufficient amount of drug to the tumor site, and rapidly releases the drug in the tumor site.
  • the liposome composition of the present invention is In an environment where glutamine degradation is enhanced and the ammonium concentration is high (5 mmol / L) like a tumor, drug release is greatly increased.
  • the release rate of the drug from the liposome in plasma with an ammonium concentration of 1 mmol / L or less is 20% / 24 hours or less at 37 ° C., and the plasma has an ammonium concentration of 4 to 6 mmol / L.
  • the release rate of the drug from the liposome is 60% or more, more preferably the release rate of the drug from the liposome in plasma having an ammonium concentration of 1 mmol / L or less is 15% / 24 hours or less at 37 ° C.
  • the release rate of the drug from the liposomes in plasma at a concentration of 4-6 mmol / L is 70% or more.
  • the method for producing the liposome composition of the present invention is not particularly limited, but as an example, (A) preparation of the oil phase; (B) preparation of the aqueous phase; (C) liposome particle formation by emulsification; (D) sizing with an extruder; (E) replacement of the aqueous liposome external phase by dialysis; (F) Encapsulation of the drug in liposome particles by remote loading; and (g) Removal of the external aqueous phase drug by dialysis: It can be manufactured by the process. (D) Sizing with an extruder may or may not be performed.
  • each component constituting the liposome diacylphosphatidylethanolamine, dihydrosphingomyelin, and cholesterols modified with a hydrophilic polymer
  • an organic solvent used in an oil phase is not specifically limited, For example, the water-soluble organic solvent arbitrarily mixed with water can be used.
  • water-soluble organic solvent examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol, glycols such as glycerin, ethylene glycol and propylene glycol, and polyethylene glycol. Examples include polyalkylene glycols. Among these, alcohols are preferable.
  • the alcohol is preferably at least one selected from ethanol, methanol, 2-propanol and t-butanol, more preferably at least one selected from ethanol, 2-propanol and t-butanol, More preferably, it is ethanol.
  • the concentration of each component constituting the liposome is not particularly limited and can be appropriately adjusted.
  • aqueous phase water (distilled water, water for injection, etc.), physiological saline, various buffer solutions or aqueous solutions of saccharides (sucrose, etc.) and mixtures thereof (aqueous solvent) can be used.
  • aqueous ammonium sulfate solution it is preferable to use an aqueous ammonium sulfate solution as the aqueous phase.
  • the buffer is not limited to organic or inorganic, but a buffer having a buffering action near the hydrogen ion concentration close to the body fluid is preferably used.
  • Phosphate buffer, Tris buffer, citric acid Examples include a buffer solution, an acetate buffer solution, and a good buffer.
  • the internal aqueous phase of the liposome may be an aqueous solution in which the liposome is dispersed when the liposome is produced, or water, physiological saline, various buffer solutions or aqueous solutions of saccharides and a mixture thereof newly added. There may be. It is preferable that the water used as the outer aqueous phase or the inner aqueous phase does not contain impurities (dust, chemical substances, etc.).
  • Physiological saline means an inorganic salt solution adjusted to be isotonic with the human body, and may further have a buffering function.
  • physiological saline examples include saline containing 0.9 w / v% (mass / volume percent) of sodium chloride, PBS, and Tris buffered physiological saline.
  • the aqueous phase includes both an outer aqueous phase and an inner aqueous phase.
  • the outer aqueous phase in the present invention means an aqueous solution in which liposomes are dispersed.
  • a solution occupying the outside of the liposome in a dispersion of liposomes stored in a vial or prefilled syringe package is the outer aqueous phase.
  • the solution occupying the outside of the liposome in the liposome dispersion is the outer aqueous phase of the dispersion dispersed at the time of administration using the attached dispersion or other solution.
  • the inner aqueous phase in the present invention means an aqueous phase in a closed vesicle separated by a lipid bilayer of a liposome.
  • the oil phase and the aqueous phase can be mixed and the aqueous solution containing lipid can be stirred and emulsified.
  • an emulsion in which the oil phase and the aqueous phase are emulsified in the O / W type (oil-in-water type) is prepared.
  • liposomes are formed by removing part or all of the organic solvent from the oil phase by evaporation. Alternatively, part or all of the organic solvent in the oil phase evaporates in the course of stirring and emulsification to form liposomes.
  • ultrasonic waves or mechanical shearing force is used for particle refinement.
  • an extruder process or a microfluidizer process through a filter having a fixed pore diameter can be performed. If an extruder or the like is used, the secondary vesicle liposomes can be separated into single vesicle liposomes.
  • the emulsification step is not limited as long as it is an emulsification step, but is preferably a step in which high shear is applied and fine particles are formed in an emulsification step including an organic solvent.
  • High shear is defined by the peripheral speed of the stirring blade of the emulsifier, and is preferably 5 m / s to 32 m / s, particularly preferably 20 m / s to 30 m / s. If necessary, liposomes can be formed by evaporating (desolving) the organic solvent used in the emulsification step.
  • the liquid temperature in the emulsification step in producing the liposome can be adjusted as appropriate, but the liquid temperature at the time of mixing the oil phase and the aqueous phase is preferably equal to or higher than the phase transition temperature of the lipid, For example, when a lipid having a phase transition temperature of 35 to 40 ° C. is used, the temperature is preferably 35 to 70 ° C.
  • the organic solvent and water may be evaporated from the aqueous solution containing liposomes.
  • the term “evaporation” as used herein may forcibly remove part or all of the organic solvent derived from the oil phase and the water derived from the aqueous phase as an evaporation step, or the organic solvent derived from the oil phase and the water derived from the aqueous phase. A part or all of these may naturally evaporate in the process of stirring and emulsification.
  • the method of evaporation is not particularly limited. For example, at least one of a step of evaporating by heating an organic solvent and water, a step of standing still or gently stirring after emulsification, and a step of performing vacuum deaeration is performed. Just do it.
  • the obtained liposome can be made uniform in particle size by using a dialysis method, a filtration method, an extrusion treatment or the like.
  • the extrusion treatment means a process of applying physical shearing force to atomize by passing the liposome through a filter having pores.
  • the liposome dispersion liquid and the filter can be rapidly atomized by keeping the temperature at a temperature higher than the phase transition temperature of the membrane constituting the liposome. Note that the sizing by the extruder may or may not be performed.
  • the liposome external aqueous phase solution may be replaced by dialysis.
  • the dialysate 0.05 to 5 mass% NaCl aqueous solution can be used, but it is not particularly limited.
  • the remote loading method means a method of producing empty liposomes in which no drug is encapsulated and introducing the drug into the liposome by adding the drug to the liposome external solution.
  • the remote loading method is not particularly limited, but a method using an ammonium salt is preferable, and a method using ammonium sulfate is more preferable.
  • the drug added to the external liquid is actively transferred to the liposome and taken into the liposome.
  • a solubility gradient, an ion gradient, a pH gradient, or the like is used as the driving force.
  • a solubility gradient, an ion gradient, a pH gradient, or the like is used.
  • a method of introducing a drug into a liposome using an ion gradient formed across a liposome membrane is used.
  • a technique in which a drug is added to liposomes that are formed in advance by a remote loading method using a Na + / K + concentration gradient.
  • a proton concentration gradient is generally used.
  • the pH of the inner side (inner aqueous phase) of the liposome membrane is lower than the outer side (outer aqueous phase) pH.
  • the pH gradient can be formed by a concentration gradient of an ammonium ion gradient or the like.
  • the liposome solution encapsulating the drug may be dialyzed to remove the drug not contained in the liposome. For example, by using a predetermined concentration of sucrose / histidine buffer as a dialysis solution, the liposome solution containing the drug is dialyzed to remove the drug present in the outer aqueous phase, and the dialysis solution is used to remove the outer aqueous phase. A substituted liposome composition can be obtained.
  • the liposome composition obtained above is preferably subjected to aseptic filtration.
  • As a filtration method an unnecessary thing can be removed from the aqueous solution containing a liposome using a hollow fiber membrane, a reverse osmosis membrane, or a membrane filter.
  • the aseptic filtration step and the aseptic filling step described below are preferably performed at a phase transition temperature or lower of the lipid constituting the liposome.
  • the lipid phase transition temperature is around 50 ° C., it is preferably about 0 to 40 ° C., and more specifically, it is preferably produced at about 5 to 30 ° C.
  • the liposome composition obtained after aseptic filtration is preferably aseptically filled for medical use.
  • a known method can be applied for aseptic filling.
  • a liposome composition suitable for medical use can be prepared by filling the container aseptically.
  • the liposome composition of the present invention may contain at least one of pharmaceutically acceptable isotonic agents, stabilizers, antioxidants, and pH adjusters in relation to the administration route. That is, the liposome composition of the present invention can be provided as a pharmaceutical composition.
  • the isotonic agent is not particularly limited, but for example, inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, mannitol, sorbitol, etc.
  • inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerol, mannitol, sorbitol, etc.
  • examples include polyols, sugars such as glucose, fructose, lactose, or sucrose.
  • the stabilizer is not particularly limited, and examples thereof include saccharides such as glycerol, mannitol, sorbitol, lactose, or sucrose.
  • antioxidant For example, ascorbic acid, uric acid, a tocopherol homologue (For example, four isomers of vitamin E, tocopherol alpha, beta, gamma, and delta) cysteine, EDTA (ethylenediaminetetraacetic acid), etc. Is mentioned.
  • the stabilizer and the antioxidant can be used alone or in combination of two or more.
  • pH adjusters examples include sodium hydroxide, citric acid, acetic acid, triethanolamine, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like.
  • the liposome composition of the present invention comprises a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, Pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, gelatin, agar, diglycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, phosphorus Acid buffered saline (PBS), sodium chloride, saccharides, biodegradable polymer, serum-free medium, pharmaceutical supplement It may contain additives which are acceptable ones.
  • a pharmaceutically acceptable organic solvent collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium
  • the container filled with the liposome composition of the present invention is not particularly limited, but is preferably a material having low oxygen permeability.
  • gas barrier layer made of plastic container, glass container, aluminum foil, aluminum vapor deposition film, aluminum oxide vapor deposition film, silicon oxide vapor deposition film, polyvinyl alcohol, ethylene vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, etc.
  • a back using a colored glass, an aluminum foil, an aluminum vapor-deposited film, or the like can be used to shield the light.
  • the gas in the container space and the chemical solution with an inert gas such as nitrogen in order to prevent oxidation due to oxygen present in the space in the container.
  • an inert gas such as nitrogen
  • the injection solution may be bubbled with nitrogen and filled into a container under a nitrogen atmosphere.
  • parenteral administration is preferable.
  • intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection
  • administration method include administration by syringe or infusion.
  • the dosage and number of administrations of the pharmaceutical composition of the present invention may be appropriately set according to the type of drug, the condition of the patient, etc., and generally 0.01 mg per day as the active ingredient drug mass. / Kg to 100 mg / kg can be set. The mass of the drug as the active ingredient can be set in the range of 2 mg to 10 mg per time. However, it is not limited to these dosages.
  • the pharmaceutical composition of the present invention can be preferably used as an anticancer agent.
  • the type of cancer to which the pharmaceutical composition of the present invention is applied is not particularly limited.
  • lung cancer particularly small cell lung cancer
  • ovarian cancer childhood solid tumor, cervical cancer, breast cancer, prostate Cancer, endometrial cancer, stomach (gastric gland) cancer
  • non-small cell lung cancer pancreatic cancer
  • squamous cell carcinoma of the cervix esophageal cancer
  • bladder cancer melanoma
  • colon cancer renal cell cancer
  • non-Hodgkin Lymphoma urothelial cancer
  • multiple myeloma acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, adult T-cell leukemia, bone marrow metastatic cancer, sarcoma, soft tissue tumor, ulcer chronic myelomonocytic
  • leukemia Hodgkin lymphoma
  • cutaneous T cell lymph and the like e.gkin lympho
  • SM stands for Sphingomyelin (COATSOME NM-10, NOF Corporation).
  • the egg-derived DHSM indicates dihydrosphingomyelin (a synthetic product obtained by hydrogenating COATSOME NM-10 (manufactured by NOF Corporation)) obtained by hydrogenating the egg-derived SM.
  • This chicken egg-derived DHSM has two alkyl chains having 16 carbon atoms, 70 to 80% of the total, and the rest is a mixture containing DHSMs having different alkyl chain lengths.
  • Fully synthetic DHSM indicates dihydrosphingomyelin produced by chemical synthesis so that the following compounds having 16-carbon and 18-carbon long-chain alkyl groups contain 98% or more.
  • DSPE-PEG SUNBRIGHT DSPE-020CN, manufactured by NOF (hereinafter referred to as DSPE-PEG) was used.
  • Cholesterol HP manufactured by Nippon Seika Co., Ltd. was used as cholesterol (indicated in the table as “Chol”).
  • the water phase prepared in (b) is heated to 65 ° C. and stirred with a magnetic stirrer (3000 rpm).
  • the whole oil phase prepared in (a) is heated to 65 ° C. with a hot plate, and the whole oil phase is sucked with a syringe and heated on the hot plate for 5 minutes.
  • the oil phase is added dropwise to the heated aqueous phase over 30 seconds.
  • Example 1 chicken egg-derived DHSM, PEG phospholipid (SUNBRIGHT DSPE-020CN, manufactured by NOF, hereinafter referred to as DSPE-PEG), and cholesterol were 11.52 g and 4.32 g, respectively. , And 4.32 g.
  • DSPE-PEG PEG phospholipid
  • (C) Liposome particle formation by emulsification The aqueous phase 1 prepared in (b1) was heated to 65 ° C., and the total amount of the oil phase prepared in (a) was added, and then mixed for 60 minutes at a peripheral speed of 26 m / s with a precision emulsification disperser. Subsequently, after adding the aqueous phase 2 at room temperature, the organic solvent and water were evaporated by continuing stirring at a peripheral speed of 0.1 m / s while heating at 65 ° C., and when the liquid was concentrated to 600 mL. Warming and agitation were stopped and evaporation was stopped.
  • Example 9 (A) Preparation of oil phase
  • 0.412 g, 0.153 g, and 0.153 g of chicken egg-derived DHSM, DSPE-PEG, and cholesterol were weighed, respectively.
  • the amounts of hen egg-derived DHSM, DSPE-PEG, and cholesterol were changed so that the ratios shown in Table 2 were obtained.
  • DiI an amount of DiI corresponding to 0.2 mol% with respect to the total lipid was weighed and dissolved in ethanol. Ethanol was added to the DiI ethanol solution to a total volume of 11.25 mL, and 3.75 mL of ethyl acetate was further added.
  • the weighed lipid and this organic solvent were mixed and heated to 60 ° C. to dissolve the lipid to obtain an oil phase.
  • the average particle diameter means a cumulant average particle diameter measured by a dynamic light scattering method.
  • the average particle size of each example and comparative example described in the table is the average particle size of cumulant measured by a dynamic light scattering method using a dense particle size analyzer FPAR-1000AS (manufactured by Otsuka Electronics Co., Ltd.) with an autosampler. The measurement results are shown in Tables 1 and 2.
  • Tables 1 and 2 show the results of measuring the sample with HPLC (High Performance Liquid Chromatography) apparatus Nexera-i LC-2040C (manufactured by Shimadzu Corporation) and quantifying the topotecan concentration.
  • HPLC High Performance Liquid Chromatography
  • Nexera-i LC-2040C manufactured by Shimadzu Corporation
  • a specific measurement method is as follows. In the liposomes of Tables 1 and 2, the ratio of the drug contained in the internal aqueous phase of the liposome to the drug in the entire liposome composition was at least 95% excluding Comparative Example 10. The comparative example 10 was 59%.
  • Measurement of the amount of topotecan in the liposome preparation Measured by liquid chromatography / ultraviolet-visible absorbance detection using a sample solution prepared by dissolving the prepared liposome solution in methanol and filtered and a standard curve standard solution prepared by diluting topotecan hydrochloride .
  • the inner aqueous phase topotecan concentration was calculated by subtracting the outer aqueous phase topotecan concentration from the total aqueous phase topotecan concentration.
  • the topotecan concentration of each aqueous phase was measured as follows. (Total aqueous phase topotecan concentration) 50 ⁇ L of the liposome dispersion was measured, 950 ⁇ L of methanol was added, and vortexed for 1 minute.
  • Measurement wavelength 382 nm
  • column Shiseido CAPCELLPAK C18 ACR 3 ⁇ m_3.0 mm * 75 mm
  • Column temperature constant temperature around 40 ° C.
  • the mobile phases A and B were both water / methanol / trifluoroacetic acid mixed solution, and the mobile phase was fed by changing the mixing ratio of the mobile phases A and B to control the concentration gradient.
  • Flow rate 1.0 mL / min
  • injection volume 10 ⁇ L
  • autosampler temperature measured at a constant temperature around 25 ° C.
  • the inner aqueous phase sulfate ion concentration was calculated by subtracting the outer aqueous phase sulfate ion concentration from the total aqueous phase sulfate ion concentration.
  • the sulfate ion concentration of each aqueous phase was measured as follows. (Total aqueous phase sulfate ion concentration) 50 ⁇ L of the liposome dispersion was measured, 950 ⁇ L of methanol was added, and sonication was performed for 15 seconds, followed by mixing. 90 ⁇ L of the liquid was measured, 810 ⁇ L of water for injection (manufactured by Hikari Pharmaceutical Co., Ltd.) was added, and sonication was performed for 30 seconds, followed by mixing.
  • aqueous phase liquid 100 ⁇ L of the liposome dispersion was measured and diluted by adding 900 ⁇ L of 5% glucose solution (manufactured by Otsuka Pharmaceutical). 450 ⁇ L of the liquid was treated by ultrafiltration, and the filtrate was used as an ion chromatography analysis sample. Centrifugation conditions are 7400 g, 5 ° C., 30 minutes. As the centrifuge, Hitachi Himac CF15RXII was used.
  • mice administered with the prepared topotecan-containing liposome (dose was 1 mg / kg as the drug amount)
  • blood was collected at 0.25, 2, 6, and 24 hours after administration.
  • the blood was centrifuged at 800 ⁇ g for 10 minutes, and plasma was collected.
  • the collected plasma was quantified for topotecan concentration using liquid chromatography / mass spectrometry / mass spectrometry (LC / MS / MS).
  • the area under the blood concentration-time curve (AUC) up to an infinite time after a single administration was calculated from the obtained topotecan concentration transition using the pharmacokinetic analysis software WinNonlin (registered trademark) (Certara).
  • AUC of the liposome described in Non-Patent Document 1 is calculated as 68152 hours ⁇ ng / mL.
  • the inner aqueous phase contains ammonium sulfate.
  • the measured value of AUC was 200,000 or more, and it was shown that high retention in blood could be achieved.
  • Comparative Examples 1 to 8 not using dihydrosphingomyelin Comparative Examples 9 and 10 in which the molar ratio of the inner aqueous phase sulfate ion to the total aqueous phase drug is less than 0.36, and diacylphosphatidylethanol modified with a hydrophilic polymer
  • Comparative Examples 11 and 12 in which no amine was used the measured value of AUC was less than 200,000, which was inferior to Examples 1 to 10.
  • a topotecan aqueous solution (drug amount 2 mg / kg) was administered.
  • Body weight and tumor volume were measured twice a week from the start of administration. The measurement results of body weight are shown in FIGS. 1 and 2, and the measurement results of tumor volume are shown in FIGS.
  • Example 11 to 16 Comparative Examples 13 to 16>
  • Example 11 to 16 except that the amounts of DHSM, DSPE-PEG, and cholesterol were changed so that the amount of cholesterol added and the amount of hen egg-derived DHSM added in the oil phase adjustment were in the ratio shown in Table 3.
  • Example 11 was prepared in the same manner as Example 1 except that the amount of cholesterol added in the oil phase adjustment and the amount of chicken egg-derived DHSM added were changed to 3.6 g of cholesterol and 12.9 g of chicken egg-derived DHSM. did.
  • the amounts of SM, DSPE-PEG, and cholesterol were changed so that the ratios shown in Table 3 were obtained.
  • Table 3 shows the results of measurement of particle diameter, total aqueous phase topotecan concentration, inner aqueous phase sulfate ion concentration, and AUC. Moreover, the value of AUC with respect to each cholesterol amount is shown in FIG.
  • the ratio of the drug contained in the internal aqueous phase of the liposome to the drug in the entire liposome composition was at least 98% except for Comparative Example 13.
  • the comparative example 13 was 68%.
  • the ratio of sulfate ions contained in the internal aqueous phase of the liposomes to sulfate ions in the entire liposome composition was at least 90% except for Comparative Example 13.
  • the comparative example 13 was 71%.
  • Example 17 to 24 Comparative Examples 17 to 24> ⁇ Preparation of liposome dispersion>
  • the amount of each lipid added in the oil phase adjustment is set as shown in Table 4
  • the drug encapsulated in the liposome particles by remote loading is set as shown in Table 4.
  • the drugs other than topotecan were prepared in the same manner as in Example 1 except that the drugs were encapsulated by the method described in ⁇ Encapsulation of anticancer drugs in liposome particles by remote loading> below.
  • Table 5 shows the lipid composition ratios of Examples 17 to 24 and Comparative Examples 17 to 24.
  • Encapsulation of each anticancer drug in liposome particles by remote loading Encapsulation of doxorubicin (Examples 19 and 20, Comparative Examples 19 and 20): Water for injection was added to doxorubicin hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 4 mg / m L. Further, 8 mol / L HCl solution was added while thoroughly stirring the solution, and the pH was adjusted to about 3 to dissolve doxorubicin hydrochloride. Liposomes were added to this doxorubicin solution at a volume ratio of 1/1, and then the dispersion adjusted to pH 7.0 was heated at 62 ° C. for 60 minutes.
  • irinotecan hydrochloride manufactured by Tokyo Chemical Industry Co., Ltd.
  • 8 mol / L HCl solution was added while thoroughly stirring the solution, and the pH was adjusted to about 3 to dissolve irinotecan hydrochloride.
  • Liposomes were added to this irinotecan solution at a volume ratio of 1/1, followed by heating at 62 ° C. for 60 minutes.
  • Table 6 shows the results of measuring AUC for Examples 17 to 22 and Comparative Examples 17 to 22 in the same manner as the method described above.
  • liposomes using DHSM have better retention in blood than SM liposomes and HSPC liposomes. As a result.
  • liposomes using fully synthetic DHSM having a purity of 98% or more of DHSM having an alkyl chain having 16 and 18 carbon atoms as DHSM can improve retention in blood as compared to hen egg-derived DHSM.
  • Table 7 shows the results of measuring the particle diameter, topotecan concentration, sulfate ion concentration, and release rate for Examples 17 to 24 and Comparative Examples 17 to 18 and 21 to 24.
  • the particle diameter, topotecan concentration, and sulfate ion concentration were measured in the same manner as described above in this example.
  • the ratio of the drug contained in the internal aqueous phase of the liposome to the drug in the entire liposome composition was at least 95%.
  • the ratio of sulfate ions contained in the internal aqueous phase of the liposomes to sulfate ions in the entire liposome composition was at least 95%.
  • the liposome preparation was diluted 20-fold in PBS buffer containing ammonium chloride at each concentration, and the release rate when incubated for 4 hours was measured. Release rate is defined as the percentage of the API concentration leaked to the outer water phase divided by the initial total aqueous phase API concentration.
  • Examples 17 and 18 and Comparative Examples 17 and 18 evaluation of topotecan-encapsulated liposomes
  • ammonium chloride 4.8 mmol / L As PBS buffer containing ammonium chloride at each concentration, in Examples 17 and 18 and Comparative Examples 17 and 18 (evaluation of topotecan-encapsulated liposomes), ammonium chloride 4.8 mmol / L, In Examples 19 and 20 and Comparative Examples 19 and 20 (evaluation of doxorubicin-encapsulated liposomes), ammonium chloride 200 mmol / L, In Examples 21 and 22 and Comparative Examples 21 and 22 (evaluation of sunitinib-encapsulated liposomes), ammonium chloride 100 mmol / L, In Examples 23 and 24 and Comparative Examples 23 and 24 (evaluation of irinotecan-encapsulated liposomes), a PBS buffer solution in which 4.8 mmol / L of ammonium chloride was dissolved was used.
  • liposomes using DHSM have a lower release rate than SM liposomes and HSPC liposomes, As a result, improvement in blood retention was expected.
  • DHSM having 16 or 18 alkyl chain DHSM having a purity of 98% or more is used as DHSM, the release rate can be greatly reduced in topotecan-encapsulated liposomes, doxorubicin-encapsulated liposomes, and irinotecan-encapsulated liposomes. Therefore, it has been found that it is more preferable in suppressing leakage in blood.
  • Example 2 ⁇ Measurement of insoluble fine particles>
  • samples were stored for 1 month after storage at 5 ° C. with a particle counter (HACH ULTRA) in liquid, and particles exceeding 10 ⁇ m and 25 ⁇ m contained in 1 vial preparation (2 mL).
  • the number of super-sized particles was measured (hereinafter, unless otherwise specified, particles having a particle size exceeding 10 ⁇ m mean particles having a particle size exceeding 10 ⁇ m.
  • Particles exceeding 25 ⁇ m are particles having a particle size exceeding 25 ⁇ m). means.).
  • Examples 2, 3, and 4 have a lipid concentration of 23 mmol / L.
  • Example 2 When summed as the number of particles per 1 ⁇ mol of lipid, 0.7 particles in Example 2 and 1.1 particles in Example 3 are about 10 ⁇ m particles.
  • Example 4 was 0.3. Moreover, about the particle
  • insoluble fine particles in one vial preparation (2 mL) were measured even in a sample of 1 month after storage at 5 ° C. In terms of the number of particles per 1 ⁇ mol of lipid, the number of particles exceeding 10 ⁇ m was 251 and greatly exceeded 150, and the number of particles exceeding 25 ⁇ m was 17 and greatly exceeded 15.
  • the release rate was calculated as a percentage of the leaked drug concentration (outer aqueous phase concentration) with respect to the total aqueous phase drug concentration.
  • the DHSM liposome encapsulating topotecan prepared in Example 17 and the HSPC liposome encapsulating doxorubicin (Doxyl (registered trademark) 20MG, Janssen Pharma) were added to plasma without addition of ammonium chloride (manufactured by LAMPIRE, mouse plasma, product name: Control and Donor).
  • Mouse Plasma in Na Hep, catalog number 7315511) and release rate in plasma in which 5 mmol / L ammonium chloride was dissolved were measured. The result is shown in FIG.
  • Doxil (registered trademark) 20MG is a liposome encapsulating doxorubicin composed of HSPC. It has been found that Doxil (registered trademark) has very little leakage in an environment simulating blood, but is hardly released even in a high ammonium environment simulating a tumor environment.
  • the liposome containing topotecan described in Example 17 of the present invention has very little leakage in an environment simulating blood and high blood retention, while a high ammonium environment simulating a tumor environment. It was very high at 86%, and it was expected that many drugs were delivered to the tumor by liposomes without leaking in the blood, and many of the drugs carried by the liposomes were released by the tumor. The results are shown in FIG.
  • a tumor obtained by transplanting the human ovarian cancer cell line ES-2 subcutaneously into a BALB / c nude mouse is collected, placed on a centrifugal filter with a pore size of 5 ⁇ m, and centrifuged at 400 g for 10 minutes.
  • a tumor interstitial fluid was obtained.
  • the topotecan liposome of the present invention prepared in Example 17 (30 ng as the drug amount) and the HSPC liposome (Doxyl (registered trademark) 20MG, Janssen Pharma) (30 ng as the drug amount) encapsulating doxorubicin, respectively.
  • the release rate when added and incubated at 37 ° C. for 24 hours was 85% in Example 17 and 6% with HSPC liposomes containing doxorubicin.
  • the release rate Differences were observed as expected.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP2018/013783 2017-03-31 2018-03-30 リポソーム組成物および医薬組成物 WO2018181963A1 (ja)

Priority Applications (14)

Application Number Priority Date Filing Date Title
CN202310994903.5A CN116763733A (zh) 2017-03-31 2018-03-30 脂质体组合物及医药组合物
BR112019020406-7A BR112019020406B1 (pt) 2017-03-31 2018-03-30 Composições lipossômicas, composição farmacêutica que compreende a dita composição lipossômica e uso da mesma para tratar câncer
CN202310994904.XA CN116763734A (zh) 2017-03-31 2018-03-30 脂质体组合物的制造方法
CN202111595172.4A CN114224840A (zh) 2017-03-31 2018-03-30 脂质体组合物及医药组合物
CN201880023073.9A CN110505869A (zh) 2017-03-31 2018-03-30 脂质体组合物及医药组合物
EP18776957.5A EP3603620A4 (en) 2017-03-31 2018-03-30 LIPOSOME COMPOSITION AND PHARMACEUTICAL COMPOSITION
KR1020197028183A KR102328463B1 (ko) 2017-03-31 2018-03-30 리포솜 조성물 및 의약 조성물
JP2019509395A JP6728482B2 (ja) 2017-03-31 2018-03-30 リポソーム組成物および医薬組成物
CA3058127A CA3058127C (en) 2017-03-31 2018-03-30 Liposome composition and pharmaceutical composition
RU2019130500A RU2734900C1 (ru) 2017-03-31 2018-03-30 Липосомальная композиция и фармацевтическая композиция
AU2018246024A AU2018246024B2 (en) 2017-03-31 2018-03-30 Liposome composition and pharmaceutical composition
US16/583,518 US11413244B2 (en) 2017-03-31 2019-09-26 Liposome composition and pharmaceutical composition
US17/079,759 US11446247B2 (en) 2017-03-31 2020-10-26 Liposome composition and pharmaceutical composition
US17/882,144 US20220370352A1 (en) 2017-03-31 2022-08-05 Liposome composition and pharmaceutical composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017069836 2017-03-31
JP2017-069836 2017-03-31

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/583,518 Continuation US11413244B2 (en) 2017-03-31 2019-09-26 Liposome composition and pharmaceutical composition

Publications (1)

Publication Number Publication Date
WO2018181963A1 true WO2018181963A1 (ja) 2018-10-04

Family

ID=63676279

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/013783 WO2018181963A1 (ja) 2017-03-31 2018-03-30 リポソーム組成物および医薬組成物

Country Status (10)

Country Link
US (3) US11413244B2 (zh)
EP (1) EP3603620A4 (zh)
JP (3) JP6728482B2 (zh)
KR (1) KR102328463B1 (zh)
CN (4) CN114224840A (zh)
AU (1) AU2018246024B2 (zh)
BR (1) BR112019020406B1 (zh)
CA (1) CA3058127C (zh)
RU (1) RU2734900C1 (zh)
WO (1) WO2018181963A1 (zh)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019244979A1 (ja) * 2018-06-20 2019-12-26 富士フイルム株式会社 薬物を内包するリポソーム組成物および免疫チェックポイント阻害剤を含む組合せ医薬
WO2020071349A1 (ja) * 2018-10-01 2020-04-09 富士フイルム株式会社 薬物を内包するリポソーム組成物およびプラチナ製剤を含む組合せ医薬
WO2020129826A1 (en) * 2018-12-17 2020-06-25 Eisai R&D Management Co., Ltd. Formulation comprising liposomes
US11446247B2 (en) 2017-03-31 2022-09-20 Fujifilm Corporation Liposome composition and pharmaceutical composition
WO2022250015A1 (ja) 2021-05-24 2022-12-01 富士フイルム株式会社 処置剤
WO2022250013A1 (ja) 2021-05-24 2022-12-01 富士フイルム株式会社 抗腫瘍剤
WO2023190709A1 (ja) * 2022-03-31 2023-10-05 エーザイ・アール・アンド・ディー・マネジメント株式会社 リポソーム組成物およびリポソームを含む医薬組成物

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115605196A (zh) * 2020-05-06 2023-01-13 纳米科技制药公司(Us) 用于治疗癌症和癌症耐药性的脂质体制剂
CN113876711A (zh) * 2020-07-01 2022-01-04 江苏长泰药业有限公司 一种盐酸阿霉素脂质体的制备工艺
US20240041769A1 (en) * 2020-12-14 2024-02-08 Nanotech Pharma Inc. Compositions and methods for delivery of anticancer agents with improved therapeutic index
JP6884496B1 (ja) * 2021-03-08 2021-06-09 ユーシービージャパン株式会社 レベチラセタムを有効成分とする注射用製剤
CN113101374B (zh) * 2021-04-08 2022-10-25 陕西科技大学 一种阿拉伯胶-明胶修饰牡丹籽油纳米脂质体及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02196713A (ja) 1988-09-28 1990-08-03 Yissum Res Dev Co Of Hebrew Univ Of Jerusalem 両親媒性分子を有効に充填かつ制御放出するリポソーム
US6355268B1 (en) 1998-09-16 2002-03-12 Alza Corporation Liposome-entrapped topoisomerase inhibitors
US7060828B2 (en) 2000-06-30 2006-06-13 Inex Pharmaceuticals Corporation Liposomal camptothecins and uses thereof
JP2008519045A (ja) 2004-11-05 2008-06-05 イネックス ファーマシューティカルズ コーポレイション 薬物リポソーム製剤を安定化するための組成物および方法
US7811602B2 (en) 2004-05-17 2010-10-12 Tekmira Pharmaceuticals Corporation Liposomal formulations comprising dihydrosphingomyelin and methods of use thereof
JP2016117005A (ja) * 2014-12-19 2016-06-30 富士フイルム株式会社 リポソームの製造方法及びリポソーム製造装置

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543152A (en) 1994-06-20 1996-08-06 Inex Pharmaceuticals Corporation Sphingosomes for enhanced drug delivery
US20080075762A1 (en) 2001-10-03 2008-03-27 Paul Tardi Compositions for delivery of drug combinations
US20070231379A1 (en) * 2002-08-29 2007-10-04 Slater James L Liposome-entrapped topoisomerase inhibitors
SI2161336T1 (sl) 2005-05-09 2013-11-29 Ono Pharmaceutical Co., Ltd. Humana monoklonska protitelesa za programirano smrt 1 (PD-1) in postopki za zdravljenje raka ob uporabi anti-PD-1 protiteles samih ali v kombinaciji z drugimi imunoterapevtiki
US20080206139A1 (en) * 2006-11-03 2008-08-28 The Penn State Research Foundation Delivery system for diagnostic and therapeutic agents
CN101485629B (zh) * 2008-01-16 2013-01-23 沈阳药科大学 一种给药系统及其制备方法
US20110159080A1 (en) 2008-06-03 2011-06-30 Colin Lowery Composition comprising liposome-entrapped doxorubicin and methods of administration
AR076634A1 (es) * 2008-11-21 2011-06-29 Medgenesis Therapeutix Inc Composiciones y metodo para tratar desordenes del sistema nervioso central
US20100249073A1 (en) 2009-03-27 2010-09-30 Robert Sabin Prophylactic and therapeutic treatment of Alzheimer's disease using phytic acid and phytate to reduce amyloid beta plaque and tau protein
DK2415470T3 (en) * 2009-03-30 2016-09-19 Eisai R&D Man Co Ltd liposome
US11357728B2 (en) * 2009-10-26 2022-06-14 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Liposome having inner water phase containing sulfobutyl ether cyclodextrin salt
WO2011092708A2 (en) * 2010-02-01 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Liposomes comprising amphipathic drugs and method for their preparation
BR112013016365A2 (pt) 2010-12-27 2018-06-26 Terumo Corp composição de lipossoma e processo para produção do mesmo
WO2013059922A1 (en) * 2011-10-25 2013-05-02 The University Of British Columbia Limit size lipid nanoparticles and related methods
CN102764234A (zh) 2012-08-03 2012-11-07 上海现代药物制剂工程研究中心有限公司 一种盐酸拓扑替康靶向脂质体制剂及其制备方法
EP2908909A1 (en) * 2012-10-19 2015-08-26 The Regents Of The University Of California Treating tumors of the central nervous system
US20160194625A1 (en) * 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Chimeric polynucleotides
CN104771361B (zh) * 2014-01-14 2018-06-01 中国科学院上海药物研究所 一种盐酸拓扑替康脂质体纳米制剂及其制备方法
AU2015240766B2 (en) 2014-04-01 2020-05-14 Children's Hospital Los Angeles Targeted polymerized nanoparticles for cancer treatment
DK3372232T3 (da) 2015-11-02 2021-06-07 Fujifilm Corp Tumorterapeutisk middel omfattende gemcitabinliposomsammensætning og kit
WO2017079303A1 (en) 2015-11-02 2017-05-11 The Cleveland Clinic Foundation Sequentially orchestrated immune checkpoint therapy for the treatment and prevention of cancer
BR112019007844A2 (pt) 2016-11-02 2019-07-16 Ipsen Biopharm Ltd tratamento de câncer gástrico usando terapias de combinação compreendendo irinotecano lipossômico, oxaliplatina, 5-fluoroacila (e leucovorina)
IL303038B1 (en) 2016-12-05 2024-04-01 G1 Therapeutics Inc Preservation of immune response during chemotherapy regimens
EP3603620A4 (en) 2017-03-31 2020-03-25 FUJIFILM Corporation LIPOSOME COMPOSITION AND PHARMACEUTICAL COMPOSITION
JP7036919B2 (ja) 2018-06-20 2022-03-15 富士フイルム株式会社 薬物を内包するリポソーム組成物および免疫チェックポイント阻害剤を含む組合せ医薬
JP7057434B2 (ja) 2018-10-01 2022-04-19 富士フイルム株式会社 薬物を内包するリポソーム組成物およびプラチナ製剤を含む組合せ医薬

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02196713A (ja) 1988-09-28 1990-08-03 Yissum Res Dev Co Of Hebrew Univ Of Jerusalem 両親媒性分子を有効に充填かつ制御放出するリポソーム
US6355268B1 (en) 1998-09-16 2002-03-12 Alza Corporation Liposome-entrapped topoisomerase inhibitors
US7060828B2 (en) 2000-06-30 2006-06-13 Inex Pharmaceuticals Corporation Liposomal camptothecins and uses thereof
US7811602B2 (en) 2004-05-17 2010-10-12 Tekmira Pharmaceuticals Corporation Liposomal formulations comprising dihydrosphingomyelin and methods of use thereof
JP2008519045A (ja) 2004-11-05 2008-06-05 イネックス ファーマシューティカルズ コーポレイション 薬物リポソーム製剤を安定化するための組成物および方法
JP2016117005A (ja) * 2014-12-19 2016-06-30 富士フイルム株式会社 リポソームの製造方法及びリポソーム製造装置

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Nanomedicine: Nanotechnology, Biology, and Medicine", vol. 11, 2015, pages: 1841 - 1850
JOHNSTON, MICHAEL ET AL.: "Characterization of the drug retention and pharmacokinetic properties of liposomal nanoparticles containing dihydrosphingomyelin", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1768, no. 5, 2007, pages 1121 - 1127, XP022026692 *
NANOMEDICINE, NANOTECHNOLOGY, BIOLOGY, AND MEDICINE, vol. 11, 2015, pages 1841 - 1850
WILLIAM C. ZAMBONI: "#C113 A Pharmacokinetics Study of a Novel Sphingomyelin/Cholesterol Liposomal Topotecan and Non-Liposomal Topotecan in Rats", AACR-EORTC INTERNATIONAL CONFERENCE, 22 October 2007 (2007-10-22)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11446247B2 (en) 2017-03-31 2022-09-20 Fujifilm Corporation Liposome composition and pharmaceutical composition
WO2019244979A1 (ja) * 2018-06-20 2019-12-26 富士フイルム株式会社 薬物を内包するリポソーム組成物および免疫チェックポイント阻害剤を含む組合せ医薬
WO2020071349A1 (ja) * 2018-10-01 2020-04-09 富士フイルム株式会社 薬物を内包するリポソーム組成物およびプラチナ製剤を含む組合せ医薬
WO2020129826A1 (en) * 2018-12-17 2020-06-25 Eisai R&D Management Co., Ltd. Formulation comprising liposomes
US10765633B2 (en) 2018-12-17 2020-09-08 Eisai R&D Management Co., Ltd Formulation comprising liposomes
WO2022250015A1 (ja) 2021-05-24 2022-12-01 富士フイルム株式会社 処置剤
WO2022250013A1 (ja) 2021-05-24 2022-12-01 富士フイルム株式会社 抗腫瘍剤
WO2023190709A1 (ja) * 2022-03-31 2023-10-05 エーザイ・アール・アンド・ディー・マネジメント株式会社 リポソーム組成物およびリポソームを含む医薬組成物

Also Published As

Publication number Publication date
BR112019020406A2 (pt) 2020-04-22
US20210038518A1 (en) 2021-02-11
KR102328463B1 (ko) 2021-11-17
US20200016079A1 (en) 2020-01-16
US20220370352A1 (en) 2022-11-24
US11446247B2 (en) 2022-09-20
EP3603620A1 (en) 2020-02-05
AU2018246024B2 (en) 2020-08-06
JP6728482B2 (ja) 2020-07-22
CA3058127A1 (en) 2018-10-04
JP2020158542A (ja) 2020-10-01
JP7278436B2 (ja) 2023-05-19
EP3603620A4 (en) 2020-03-25
JP2022043357A (ja) 2022-03-15
US11413244B2 (en) 2022-08-16
AU2018246024A1 (en) 2019-10-17
BR112019020406B1 (pt) 2021-10-26
CN114224840A (zh) 2022-03-25
CN116763733A (zh) 2023-09-19
CN110505869A (zh) 2019-11-26
RU2734900C1 (ru) 2020-10-26
CA3058127C (en) 2022-07-05
JP7012124B2 (ja) 2022-01-27
CN116763734A (zh) 2023-09-19
KR20190120319A (ko) 2019-10-23
JPWO2018181963A1 (ja) 2020-01-16

Similar Documents

Publication Publication Date Title
JP7278436B2 (ja) リポソーム組成物および医薬組成物
KR20180054873A (ko) 젬시타빈 리포솜 조성물을 포함하는 종양 치료제 및 키트
US20210213051A1 (en) Combined pharmaceutical formulation comprising drug-containing liposome composition and platinum preparation
WO2015166985A1 (ja) リポソーム組成物及びその製造方法
JP6705933B2 (ja) リポソーム組成物およびその製造方法
JP7036919B2 (ja) 薬物を内包するリポソーム組成物および免疫チェックポイント阻害剤を含む組合せ医薬
TWI837189B (zh) 包含內含藥物之脂質體組成物及鉑製劑之組合醫藥
JP7343643B2 (ja) 脂質粒子組成物および医薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18776957

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019509395

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20197028183

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 3058127

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112019020406

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2018246024

Country of ref document: AU

Date of ref document: 20180330

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2018776957

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2018776957

Country of ref document: EP

Effective date: 20191031

ENP Entry into the national phase

Ref document number: 112019020406

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20190927